Angioaccess vascular grafts are used to provide access for chronic hemodialysis. However, angioaccess vascular grafts (AVGs) occlude frequently due to development on intimal hyperplasia at the distal venous anastomosis. In this proposal, the investigators seeks to use genetic strategies to test molecular hypotheses regarding the mechanisms giving rise to stenotic vascular lesions in AVGs. The molecular reactions leading to neointima formation in AVGs are probably similar to the processes of vascular lesion formation (NVLF) occurring in other settings after mechanical injury. Genetic interventions will be developed to prevent AVG failure, to assess the role of specific molecular mechanisms of AVG-induced thrombosis and NVLF in non-human primates. The model involves the surgical placement of externally reinforced expanded polytetrafluorethylene (EPTFE) vascular grafts between arteries and veins with quantitation of thrombosis and vascular lesion development. Two approaches will be used to interrupt thrombosis and NVLF at AVG-venous anastomoses: (a) genetically modified confluent Ecs lining the AVGs that secrete transduced gene products continuously into the local microenvironment; (b) extended local delivery of antisense oligonucleotides for hours-to-days using a novel and fusion catheter. Both approaches have been shown to maintain constant high concentrations in the fluid boundary layer at the vascular wall-blood interface, levels which are typically several orders of magnitude greater than those achieved systemically. The catheter-based approach delivers therapeutic agents into the slowest moving blood layers along the vessel wall, thereby stimulating the fluid mechanical advantage for molecules released from the vessel wall itself. It is also an efficient method to assess in vivo the effects of substances which could be expressed by genetically-enhanced Ecs in situ. They postulate that: (a) anti-thrombotic and anti-lesion affects will be produced in situ by autologous endothelial cells expressing retrovirally-transduced hirudin or an anti-thrombin peptide comprising the thrombin receptor binding sequence, or inhibiting platelet recruitment via the increased production of nitric oxide or antioxidant activities; (b) NVFL will be reduced by antisense oligonucleotides targeting vascular cell expression of thrombin receptors via a local delivery catheter.